PROJECT SUMMARY: Aerobic exercise capacity declines progressively with advancing age eventually leading to increased disability, loss of independence, and reduced quality of life in older adults. The overall goal of this research program is to investigate the mechanism(s) involved in the impaired control of muscle blood flow and vascular tone during dynamic exercise in aging humans. This proposal seeks to mechanistically-link oxidative stress-induced peripheral endothelial dysfunction with impaired vascular control during dynamic exercise in aging humans. The general concept is that age-associated increases in oxidative stress reduce endothelium-derived nitric oxide (NO) bioavailability and cause the production of cyclooxygenase-derived vasoconstrictor prostaglandins (PCs), thus impairing local vasodilator responses during exercise in older adults. To test our hypotheses we will address the following specific aims: (1) we will determine whether the impaired control of muscle blood flow and vascular tone observed during dynamic exercise in older adults is due to age-related impairments in endothelium-dependent vasodilation, and specifically, we will determine the independent and interactive contribution of NO and PGs to this impairment; (2) we will determine whether acute reductions in oxidative stress in older adults improves endothelial vasodilator function and therefore, improves muscle blood flow and local vasodilator responses during exercise. The methods employed to address these aims are state-of-the-art and involve local (intra- arterial) administration of various study drugs during exercise to investigate the roles of NO, PGs, and oxidative stress in the control of muscle blood flow in young and older healthy humans. The findings from the proposed studies should provide unique insight into the regulation of muscle blood flow and vascular control during exercise in aging humans, and also could have significant implications for the understanding and treatment of exercise intolerance in diseased populations that also demonstrate endothelial dysfunction (e.g., heart failure patients). RELEVANCE: Aging is associated with a reduced quality of life which is due, in part, to reductions in exercise capacity. The studies in this application are designed to understand the potential contribution of impaired blood vessel function to exercise intolerance in older adults, and will provide ideas on how to prevent or improve this function, thereby enhancing the quality of life of older adults. [unreadable] [unreadable]